David Arterburn

Meta-analysis : Pharmacologic treatment of obesity

Context The effectiveness of pharmacologic therapy in the treatment of obesity is unclear. Contribution This review of 79 clinical trials involving diet plus the obesity drugs sibutramine, orlistat, fluoxetine, sertraline, bupropion, topiramate, or zonisamide shows that these medications can lead to modest weight reductions of approximately 5 kg or less at 1 year. Available evidence is lacking on the effect of these drugs on long-term weight loss, health outcomes such as cardiovascular events and diabetes, and adverse effects. Implications Those considering pharmacologic treatment for obesity should understand that these drugs can lead to modest weight loss at 1 year, but data on long-term effectiveness and safety are lacking. The Editors Obesity has been defined as excess body fat relative to lean body mass (1) and, in humans, is the result of interactions of the environment with multiple genes. The age-adjusted prevalence of obesity was 30.5% in 19992000 (2). Although it is difficult to precisely estimate the change in prevalence of obesity over time because of changing definitions, nearly all clinical authorities agree that obesity is reaching epidemic proportions (2-13). Obesity is currently defined as a body mass index (BMI) of 30 kg/m2 or greater. Individuals whose BMI falls between 25 kg/m2 and 29.9 kg/m2 are considered overweight. Attempts to meet the body weight goal of the Healthy People 2000 initiative (7)to reduce the prevalence of overweight among adults to less than 20% of the populationdid not succeed. Still, many Americans are trying. According to a national survey (14), about 40% of women and 25% of men reported that they were currently trying to lose weight. However, most weight loss attempts consist of 6 months of loss followed by gradual regain to baseline (15). The health consequences of obesity include some of the most common chronic diseases in our society. Obesity is an independent risk factor for heart disease (16). Type 2 diabetes mellitus, hypertension and stroke, hyperlipidemia, osteoarthritis, and sleep apnea are all more common in obese individuals (17-19). A recent prospective study involving 900000 U.S. adults reported that increased body weight was associated with increased death rates for all cancer combined and for cancer at multiple specific sites (20). Adult weight gain is associated with increased risk for breast cancer in postmenopausal women (21). Weight loss of 5% to 10% can be associated with marked reductions in the risk for these chronic diseases (22). In the Diabetes Prevention Program, weight loss of about 5% to 6% among persons with a BMI of 34 kg/m2, along with increased physical activity, resulted in a 58% reduction in the incidence of diabetes (23). In response to the increase in obesity, pharmaceutical treatments for obesity have become both more numerous and more commonly used. Drugs prescribed for weight loss can be divided into 2 categoriesappetite suppressants and lipase inhibitorson the basis of their putative mechanisms of action. Appetite suppressants can be further subdivided on the basis of the neurotransmitters they are believed to affect. This article, which reviews the available evidence on medications used as obesity treatment in adults (Table 1), is part of a larger evidence report prepared for the Agency for Healthcare Research and Quality titled Pharmacological and Surgical Treatment of Obesity. The larger report is available at www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1a.chapter.19289. Table 1. Prescription Medications Used for Weight Loss Methods Literature Search and Selection Our search for controlled human studies of pharmacologic treatments of obesity began with an electronic search of MEDLINE on 16 October 2002. Subsequently, our librarian conducted current awareness search updates on 22 May, 2 June, 12 June, and 3 July 2003. We also searched the Cochrane Controlled Clinical Trials Register Database and existing systematic reviews. Full details of the search strategy are available in the larger evidence report. To be accepted for analysis, a study of drug therapy had to be a controlled clinical trial that assessed the effect of one of the pharmaceutical agents in humans and reported at least 6-month weight loss outcomes in pounds or kilograms. We made an exception for topiramate, for which most trials reported only percentage of weight loss. Patients in included studies needed to have a BMI of 27 kg/m2 or greater (Appendix Table). The technical expert panel for our evidence report determined which pharmaceutical agents would be included. The panel chose sibutramine, orlistat, phentermine, and diethylpropion, all of which have been approved by the U.S. Food and Drug Administration, as well as other medications being used for weight loss, including fluoxetine, bupropion, sertraline, topiramate, and zonisamide. Extraction of Study-Level Variables and Results Three reviewers, working in groups of 2, extracted data from the same articles and resolved disagreements by consensus. A senior physician resolved any remaining disagreements. We used the Jadad score to evaluate the quality of the studies, using information on study design, method of random assignment, blinding, and withdrawal (34). Jadad scores range from 0 (lowest quality) to 5 (highest quality). We also collected information on withdrawal and dropout rates and calculated the percentage of attrition by dividing the number of patients providing follow-up data by the number of patients initially enrolled. Of the medications we assessed, 3 had up-to-date existing meta-analyses (sibutramine, phentermine, and diethylpropion) and 4 others had a sufficient number of new studies to justify a new meta-analysis (orlistat, fluoxetine, bupropion, and topiramate). However, because heterogeneity was too great for the fluoxetine studies, they are summarized narratively. Selection of Trials for Meta-Analysis The outcome of interest was weight loss between baseline and follow-up. To make our analyses comparable, we stratified them in the same manner as did the recent meta-analysis on sibutramine (35). We defined data collected at 6 months to be data collected at any point between 16 and 24 weeks; likewise, 1-year follow-up data were those collected at any point between 44 and 54 weeks. If a study presented data for 2 or more time points in an interval, for example, 16 and 18 weeks, we chose the longest follow-up measurement for our analysis. Mean Difference For each trial, we extracted the follow-up mean weight loss for the control group, the follow-up mean weight loss for the medication group, and the standard deviation for each group. We then calculated a mean difference for each study, which was the difference between follow-up mean weight loss in the control group versus the medication group. Sensitivity Analyses We conducted sensitivity analyses on 4 study dimensions: Jadad quality score (2 vs. 3), year of publication (1998 or earlier vs. 1999 or later), completion rate (<80% vs. 80% and <70% vs. 70%), and dosage. We tested for differences between subgroups (for example, high-quality vs. lower-quality studies) by conducting a meta-regression analysis using a single dichotomous variable to indicate subgroup membership. We conducted sensitivity analyses to determine the possible impact of dropouts. In these analyses, we assumed that all patients who dropped out had a weight loss of zero. The mean weight loss for a particular study was then recalculated on the basis of the complete sample of both responders and dropouts. We assumed that the standard deviation of weight loss for a study did not change and recalculated the standard error on the basis of the complete sample size. We then conducted a pooled analysis for each medication and follow-up time as performed in the original approach. Meta-Analysis of Weight Loss For the 6-month and 12-month analyses, we estimated a pooled DerSimonianLaird random-effects estimate (36) of the overall mean difference. The mean differences in the individual trials are weighted by both within-study variation and between-study variation in this synthesis. We also report P values derived from the chi-square test of heterogeneity based on the Cochran Q-test (37), and the I2 statistic (38). This latter statistic represents the percentage of study variability that is due to heterogeneity rather than chance and is independent of the number of studies and the effect size metric. Publication Bias We assessed the possibility of publication bias by evaluating a funnel plot. We also conducted an adjusted rank correlation test (39) as a formal statistical test for publication bias. Extraction of Data on Adverse Events We assessed evidence of adverse events from randomized, controlled trials (RCTs) only. We did not include observational studies or case series data. Each trial included in the weight loss analysis was examined to determine whether it reported data on adverse events. Adverse events were recorded as the number of events or the number of people, depending on how the trial chose to report events. Most trials recorded the number of events rather than the number of unique people who experienced the event. Each event was counted as if it represented a unique individual. Because a single individual might have experienced more than 1 event, this assumption may have overestimated the number of people who had an adverse event. Meta-Analysis of Adverse Events For subgroups of events that occurred in 2 or more trials, at least once in the medication group and at least once in the control group, we performed a meta-analysis to estimate the pooled odds ratio and its associated 95% CI. Given that many of the events were rare, we used exact conditional inference to perform the pooling rather than applying the usual asymptotic methods that assume normality. For interpretability, for any significant pooled odds ratio greater than 1 (which indicates that the odds of the adverse

The coming epidemic of obesity in elderly Americans

Objectives: To estimate the prevalence of obesity in elderly Americans in 2010 and to discuss the health and economic implications of these estimates.

Impact of morbid obesity on medical expenditures in adults.

CONTEXT:Morbid obesity (body mass index (BMI) ≥40 kg/m2) is associated with substantially increased morbidity and mortality from chronic health conditions and with poorer health-related quality of life; however, less is known about the impact of morbid obesity on healthcare expenditures.OBJECTIVE:To examine the impact of morbid obesity on healthcare expenditures using a nationally representative sample of US adults.DESIGN, SETTING, AND PARTICIPANTS:We performed a cross-sectional analysis of 16 262 adults from the 2000 Medical Expenditure Panel Survey, a nationally representative survey of the noninstitutionalized civilian population of the United States. Per capita healthcare expenditures were calculated for National Institutes of Health BMI categories, based on self-reported height and weight, using a two-part, multivariable model adjusted for age, gender, race, income, education level, type of health insurance, marital status, and smoking status.MAIN OUTCOME MEASURES:Odds of incurring any healthcare expenditure and per capita healthcare expenditures associated with morbid obesity in 2000.RESULTS:When compared with normal-weight adults, the odds of incurring any healthcare expenditure in 2000 were two-fold greater among adults with morbid obesity. Per capita healthcare expenditures for morbidly obese adults were 81% (95% confidence interval (CI): 48–121%) greater than normal-weight adults, 65% (95% CI: 37–110%) greater than overweight adults, and 47% (95% CI: 11–96%) greater than adults with class I obesity. Excess costs among morbidly obese adults resulted from greater expenditures for office-based visits, outpatient hospital care, in-patient care, and prescription drugs. Aggregate US healthcare expenditures associated with excess body weight among morbidly obese US adults exceeded

Association Between Bariatric Surgery and Long-term Survival

11 billion in 2000.CONCLUSIONS:The economic burden of morbid obesity among US adults is substantial. Further research is needed to identify interventions to reduce the incidence and prevalence of morbid obesity and improve the health and economic outcomes of morbidly obese adults.

Child obesity associated with social disadvantage of children's neighborhoods

IMPORTANCE Accumulating evidence suggests that bariatric surgery improves survival among patients with severe obesity, but research among veterans has shown no evidence of benefit. OBJECTIVE To examine long-term survival in a large multisite cohort of patients who underwent bariatric surgery compared with matched control patients. DESIGN, SETTING, AND PARTICIPANTS In a retrospective cohort study, we identified 2500 patients (74% men) who underwent bariatric surgery in Veterans Affairs (VA) bariatric centers from 2000-2011 and matched them to 7462 control patients using sequential stratification and an algorithm that included age, sex, geographic region, body mass index, diabetes, and Diagnostic Cost Group. Survival was compared across patients who underwent bariatric surgery and matched controls using Kaplan-Meier estimators and stratified, adjusted Cox regression analyses. EXPOSURES Bariatric procedures, which included 74% gastric bypass, 15% sleeve gastrectomy, 10% adjustable gastric banding, and 1% other. MAIN OUTCOMES AND MEASURES All-cause mortality through December 2013. RESULTS Surgical patients (n = 2500) had a mean age of 52 years and a mean BMI of 47. Matched control patients (n = 7462) had a mean age of 53 years and a mean BMI of 46. At the end of the 14-year study period, there were a total of 263 deaths in the surgical group (mean follow-up, 6.9 years) and 1277 deaths in the matched control group (mean follow-up, 6.6 years). Kaplan-Meier estimated mortality rates were 2.4% at 1 year, 6.4% at 5 years, and 13.8% at 10 years for surgical patients; for matched control patients, 1.7% at 1 year, 10.4% at 5 years, and 23.9% at 10 years. Adjusted analysis showed no significant association between bariatric surgery and all-cause mortality in the first year of follow-up (adjusted hazard ratio [HR], 1.28 [95% CI, 0.98-1.68]), but significantly lower mortality after 1 to 5 years (HR, 0.45 [95% CI, 0.36-0.56]) and 5 to 14 years (HR, 0.47 [95% CI, 0.39-0.58]). The midterm (>1-5 years) and long-term (>5 years) relationships between surgery and survival were not significantly different across subgroups defined by diabetes diagnosis, sex, and period of surgery. CONCLUSIONS AND RELEVANCE Among obese patients receiving care in the VA health system, those who underwent bariatric surgery compared with matched control patients who did not have surgery had lower all-cause mortality at 5 years and up to 10 years following the procedure. These results provide further evidence for the beneficial relationship between surgery and survival that has been demonstrated in younger, predominantly female populations.

Survival Among High-Risk Patients After Bariatric Surgery

Evidence suggests variability in adult obesity risk at a small-scale geographic area is associated with differences in neighborhood socioeconomic status (SES). However, the extent to which geographic variability in child obesity is associated with neighborhood SES is unknown. The objective of this paper was to estimate risk of child obesity associated with multiple census tract SES measures and race within a large urban U.S. county. Height, weight, age, sex, medical insurance type and census tract residence were obtained for 6-18 year old children (n=8616) who received medical care at a health plan in King County, Washington, in 2006. Spatial analyses examined the individual risk of obesity (BMI > or = 95th percentile) with 2000 US census tract measures of median household income, home ownership, adult female education level, single parent households, and race as predictors. Conditional autoregressive regression models that incorporated adjacent census tracts (spatial autocorrelation) were applied to each census tract variable, adjusting for individual variables. We found that in adjusted spatial models, child obesity risk was significantly associated with each census tract variable in the expected direction: lower household income, lower home ownership, and for each 10% increase in less educated women, and single parent households, as well as non-white residents. In a spatial model including all variables, the SES/race variables explained approximately 24% of geographic variability in child obesity. Results indicated that living in census tracts with social disadvantage defined by multiple different measures was associated with child obesity among insured children in a large U.S. urban county. These results contribute new information on relationships between broader social and economic context and child obesity risk using robust spatial analyses.

Long-term Outcomes of Bariatric Surgery: A National Institutes of Health Symposium

CONTEXT Existing evidence of the survival associated with bariatric surgery is based on cohort studies of predominantly younger women with a low inherent obesity-related mortality risk. The association of survival and bariatric surgery for older men is less clear. OBJECTIVE To determine whether bariatric surgery is associated with reduced mortality in a multisite cohort of predominantly older male patients who have a high baseline mortality rate. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of bariatric surgery programs in Veterans Affairs medical centers. Mortality was examined for 850 veterans who had bariatric surgery in January 2000 to December 2006 (mean age 49.5 years; SD 8.3; mean body mass index [BMI] 47.4; SD 7.8) and 41,244 nonsurgical controls (mean age 54.7 years, SD 10.2; mean BMI 42.0, SD 5.0) from the same 12 Veteran Integrated Service Networks; the mean follow-up was 6.7 years. Four Cox proportional hazards models were assessed: unadjusted and controlled for baseline covariates on unmatched and propensity-matched cohorts. MAIN OUTCOME MEASURE All-cause mortality through December 2008. RESULTS Among patients who had bariatric surgery, the 1-, 2-, and 6-year crude mortality rates were, respectively, 1.5%, 2.2%, and 6.8% compared with 2.2%, 4.6%, and 15.2% for nonsurgical controls. In unadjusted Cox regression, bariatric surgery was associated with reduced mortality (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.51-0.80). After covariate adjustment, bariatric surgery remained associated with reduced mortality (HR, 0.80; 95% CI, 0.63-0.995). In analysis of 1694 propensity-matched patients, bariatric surgery was no longer significantly associated with reduced mortality in unadjusted (HR, 0.83; 95% CI, 0.61-1.14) and time-adjusted (HR, 0.94; 95% CI, 0.64-1.39) Cox regressions. CONCLUSION In propensity score-adjusted analyses of older severely obese patients with high baseline mortality in Veterans Affairs medical centers, the use of bariatric surgery compared with usual care was not associated with decreased mortality during a mean 6.7 years of follow-up.

Perceived Barriers to Weight Management in Primary Care—Perspectives of Patients and Providers

IMPORTANCE The clinical evidence base demonstrating bariatric surgerys health benefits is much larger than it was when the National Institutes of Health last held a consensus panel in 1991. Still, it remains unclear whether ongoing studies will address critical questions about long-term complication rates and the sustainability of weight loss and comorbidity control. OBJECTIVE To summarize findings from a multidisciplinary workshop convened in May 2013 by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute. The workshop aimed to summarize the current state of knowledge of bariatric surgery, review research findings on the long-term outcomes of bariatric surgery, and establish priorities for future research directions. EVIDENCE REVIEW The evidence presented at the workshop was selected by the planning committee for both its quality and duration of follow-up. The data review emphasized randomized clinical trials and large observational studies with long-term follow-up, with or without a control group. FINDINGS Several small randomized clinical trials showed greater weight loss and type 2 diabetes mellitus remission compared with nonsurgical treatments within the first 2 years of follow-up after bariatric surgery. Large, long-term observational studies have shown durable (>5 years) weight loss, diabetes, and lipid improvements with bariatric surgery. Still unclear are predictors of outcomes, long-term complications, long-term survival, microvascular and macrovascular events, mental health outcomes, and costs. The studies needed to address these knowledge gaps would be expensive and logistically difficult to perform. CONCLUSIONS AND RELEVANCE High-quality evidence shows that bariatric surgical procedures result in greater weight loss than nonsurgical treatments and are more effective at inducing initial type 2 diabetes mellitus remission in obese patients. More information is needed about the long-term durability of comorbidity control and complications after bariatric procedures and this evidence will most likely come from carefully designed observational studies.

Bariatric surgery for obesity and metabolic conditions in adults

BackgroundDespite the consequences of overweight and obesity, effective weight management is not occurring in primary care.ObjectiveTo identify beliefs about obesity that act as barriers to weight management in primary care by surveying both patients and providers and comparing their responses.DesignAnonymous, cross-sectional, self-administered survey of patients and providers of a Veteran’s Administration Primary Care Clinic, distributed at the clinic site.SubjectsForty-eight Internal Medicine providers and 488 patients.MeasurementsBeliefs, attitudes, and experiences with weight management as well as demographic characteristics were collected through a questionnaire.ResultsProviders and patients differed significantly on many beliefs about weight. Providers were more likely than patients to perceive that patients lack self-control to stay on a diet and that fattening food in society and lack of time for exercise were prime factors in weight gain. They also expressed more interest in helping patients with weight management than patients desiring this. Patients were more likely to state that weight problems should be managed on one’s own, talking to a provider is not helpful, providers blame them for their weight problem, and that appointments contain sufficient time for weight discussion.ConclusionProviders and patients emphasize different barriers to weight management. Providers need to be aware of the beliefs that their patients hold to improve weight management discussions and interventions in primary care.

Bariatric Surgery and Long-term Durability of Weight Loss

This review summarizes recent evidence related to the safety, efficacy, and metabolic outcomes of bariatric surgery to guide clinical decision making. Several short term randomized controlled trials have demonstrated the effectiveness of bariatric procedures for inducing weight loss and initial remission of type 2 diabetes. Observational studies have linked bariatric procedures with long term improvements in body weight, type 2 diabetes, survival, cardiovascular events, incident cancer, and quality of life. Perioperative mortality for the average patient is low but varies greatly across subgroups. The incidence of major complications after surgery also varies widely, and emerging data show that some procedures are associated with a greater risk of substance misuse disorders, suicide, and nutritional deficiencies. More research is needed to enable long term outcomes to be compared across various procedures and subpopulations, and to identify those most likely to benefit from surgical intervention. Given uncertainties about the balance between the risks and benefits of bariatric surgery in the long term, the decision to undergo surgery should be based on a high quality shared decision making process.